Aripiprazole crystalline forms

ABSTRACT

The present invention provides novel crystalline forms of aripiprazole and processes for their preparation.

FIELD OF THE INVENTION

The present invention provides novel crystalline forms of aripiprazoleand processes for their preparation.

BACKGROUND OF THE INVENTION

Aripiprazole of formula (1):

or7-[4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolinoneand its salts are useful for treating schizophrenia and theirtherapeutic uses were disclosed in U.S. Pat. No. 5,006,528.

Processes for the preparation of aripiprazole and its salts weredescribed in U.S. Pat. No. 5,006,528. Various crystalline forms ofaripiprazole and its hydrates were disclosed in WO 03/026659, JapaneseUnexamined Patent Publication No. 191256/1990 and 4^(th) Japanese-KoreanSymposium on Separation Technology (Oct. 6-8, 1996).

We have discovered a novel crystalline form of aripiprazole,aripiprazole methanolate and aripiprazole ethylene dichloride solvate.The novel crystalline form of aripiprazole is non hygroscopic, do nothave the tendency to convert to other forms and suitable forpharmaceutical preparations.

The methanolate and ethylene dichloride solvate are non-hygroscopic,obtainable in pure form and can be converted to crystalline forms ofaripiprazole and aripiprazole hydrates.

Therefore, the solvates are useful as intermediates for preparing purearipiprazole or aripiprazole hydrates in any crystalline form.

Thus, one object of the present invention is to provide stable,non-hygroscopic crystalline form of aripiprazole, process for preparingthis form and pharmaceutical compositions containing it.

Another object of the present invention is to provide aripiprazolemethanolate and aripiprazole ethylenedichloride solvate and process forpreparing the solvates; and use of these solvates to prepare other formsof aripiprazole.

DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided a novelcrystalline form of aripiprazole. The crystalline form is designated asaripiprazole form III and typical form III x-ray powder diffractionspectrum of aripiprazole form III is shown in FIG. 1.

Aripiprazole form III is characterized by peaks in the powder x-raydiffraction spectrum having 2θ angle positions at about 8.8, 11.2, 11.4,11.9, 13.6, 14.4, 15.0, 15.9, 16.4, 17.8, 18.7, 20.4, 20.8, 21.4, 22.2,23.5, 25.0, 25.9 and 26.5 degrees.

In accordance with the present invention, there is provided a processfor preparation of the aripiprazole form III comprising the steps of:

-   a) preparing a solution of aripiprazole in a mixture of methyl    tert-butyl ether, acetonitrile and tetrahydrofuran; and-   b) isolating aripiprazole form III from the solution.

Aripiprazole used in the process can be in any of the crystalline forms.Aripiprazole solvate or hydrate form can also be used in the process toproduce aripiprazole form III.

The solution of aripiprazole is usually prepared at elevatedtemperature, preferably at reflux temperature and then the solution iscooled preferably to 0° C. to 30° C., more preferably to 15° C. to 30°C. The precipitated form III crystals are collected by filtration orcentrifugation.

In accordance with the present invention, there is provided aripiprazolemethanolate. The content of methanol is between about 2 to 6% of theweight of aripiprazole methanolate. Aripiprazole methanolate typicallyshows a crystalline form, which is designated as aripiprazolemethanolate form IV and typical form IV x-ray powder diffractionspectrum of aripiprazole methanolate form IV is shown in FIG. 2.

Aripiprazole methanolate form IV is characterized by peaks in the powderx-ray diffraction spectrum having 2θ angle positions at about 9.8, 11.0,11.8, 12.1, 12.6, 13.6, 17.4, 18.8, 20.1, 23.3, 24.6, 25.0, 25.9, 27.2,28.4, 29.3, 30.1 and 31.5 degrees.

In accordance with the present invention, there is provided a processfor preparation of the aripiprazole methanolate form IV comprising thesteps of:

-   a) preparing a solution of aripiprazole in a mixture of methanol and    tetrahydrofuran; and-   b) isolating aripiprazole methanolate form IV from the solution.

The solution of aripiprazole is usually prepared at elevatedtemperature, preferably at reflux temperature and then the solution iscooled preferably to 0° C. to 30° C. The precipitated form IV crystalsare collected by filtration or centrifugation.

Aripiprazole methanolate can be used to prepare aripiprazole forms bycrystallizing from the appropriate solvent system. Thus, for examplearipiprazole form III can be prepared by preparing a solution ofaripiprazole methanolate in a mixture of methyl tert-butyl ether,acetonitrile and tetrahydrofuran and isolating aripiprazole form IIIfrom the solution.

In accordance with the present invention, there is provided aripiprazoleethylenedichloride solvate. The content of ethylenedichloride is betweenabout 15 to 40% of the weight of aripiprazole ethylenedichloridesolvate. Aripiprazole ethylenedichloride solvate typically shows acrystalline form, which is designated as aripiprazole ethylenedichloridesolvate form V and the typical form V x-ray powder diffraction spectrumof aripiprazole ethylenedichloride solvate form V is shown in FIG. 3.

Aripiprazole ethylenedichloride solvate form V is characterized by peaksin the powder x-ray diffraction spectrum having 2θ angle positions atabout 10.7, 17.6, 17.8, 20.6, 22.1, 23.4, 24.7 and 26.4 degrees.

In accordance with the present invention, there is provided a processfor preparation of the Aripiprazole ethylenedichloride solvate form Vcomprising the steps of:

-   a) preparing a solution of aripiprazole in ethylenedichloride and-   b) isolating aripiprazole ethylenedichloride solvate form V from the    solution.

The solution of aripiprazole is usually prepared at elevatedtemperature, preferably at reflux temperature and then the solution iscooled preferably to 0° C. to 30° C. The precipitated form V crystalsare collected by filtration or centrifugation.

Aripiprazole aripiprazole ethylenedichloride solvate can be used toprepare aripiprazole forms by crystallizing from the appropriate solventsystem. Thus, for example aripiprazole form III can be prepared bypreparing a solution of aripiprazole ethylenedichloride in a mixture ofmethyl tert-butyl ether, acetonitrile and tetrahydrofuran and isolatingaripiprazole form III from the solution.

In accordance with the present invention, there is provided apharmaceutical composition comprising aripiprazole form III and apharmaceutically acceptable carrier or diluent.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a x-ray powder diffraction spectrum of aripiprazole form III.

FIG. 2 is a x-ray powder diffraction spectrum of aripiprazolemethanolate form IV.

FIG. 3 is a x-ray powder diffraction spectrum of aripiprazoleethylenedichloride solvate form V.

x-Ray powder diffraction spectrum was measured on a Bruker axs D8advance x-ray powder diffractometer having a copper-Kα radiation.

The invention will now be further described by the following examples,which are illustrative rather than limiting.

EXAMPLE 1

Aripiprazole (3 gm) is mixed with methyl tert-butyl ether (25 ml) andheated to reflux temperature. Then acetonitrile (45 ml) andtetrahydrofuran (25 ml) are added to the mixture and heated to about 55°C. to form a clear solution. The solution is slowly cooled to 25° C.,stirred for 1 hour at about 25° C. and the precipitated crystals arecollected by filtration to give 2 gm of aripiprazole form III.

EXAMPLE 2

Aripiprazole (3 gm), obtained by a known method is mixed with methanol(30 ml) and heated to reflux temperature. Then tetrahydrofuran (25 ml)is added at the same temperature to form a clear solution. The solutionis slowly cooled to about 25° C., stirred for 1 hour at about 25° C. andthe separated crystals are collected by filtration to give 2.9 gm ofaripiprazole methanolate form IV.

EXAMPLE 3

Example 1 is repeated using aripiprazole methanolate obtained as inexample 2 instead of aripiprazole to give aripiprazole form III.

EXAMPLE 4

Aripiprazole (3 gm) is mixed with ethylenedichloride (30 ml) and heatedto 50° C. to form a clear solution. The solution is slowly cooled to 25°C., stirred for 1 hour at about 25° C. and the separated crystals arecollected by filtration to give 2.5 gm of aripiprazoleethylenedichloride solvate form V.

EXAMPLE 5

Example 1 is repeated using aripiprazole ethylenedichloride solvateobtained as in example 4 instead of aripiprazole to give aripiprazoleform III.

1. Aripiprazole methanolate.
 2. Aripiprazole methanolate of claim 1,wherein methanol content is between about 2 to 6% of the weight ofaripiprazole methanolate.
 3. A process for preparation of aripiprazolemethanolate, which comprises the steps of: a) preparing a solution ofaripiprazole in a mixture of methanol and tetrahydrofuran; and b)isolating aripiprazole methanolate from the solution.